A predictably selective aliphatic C-H oxidation reaction for complex molecule synthesis

Realizing the extraordinary potential of unactivated sp3 C-H bond oxidation in organic synthesis requires the discovery of catalysts that are both highly reactive and predictably selective. We report an iron (Fe)-based small molecule catalyst that uses hydrogen peroxide (H2O2) to oxidize a broad range of substrates. Predictable selectivity is achieved solely on the basis of the electronic and steric properties of the C-H bonds, without the need for directing groups. Additionally, carboxylate directing groups may be used to furnish five-membered ring lactone products. We demonstrate that these three modes of selectivity enable the predictable oxidation of complex natural products and their derivatives at specific C-H bonds with preparatively useful yields. This type of general and predictable reactivity stands to enable aliphatic C-H oxidation as a method for streamlining complex molecule synthesis.     

Activation of alkanes with organotransition metal complexes

Alkanes, although plentiful enough to be considered for use as feedstocks in large-scale chemical processes, are so unreactive that relatively few chemical reagents have been developed to convert them to molecules having useful functional groups. However, a recently synthesized iridium (lr) complex successfully converts alkanes into hydridoalkylmetal complexes (M + R-H --> R-M-H). This is a dihydride having the formula Cp(*)(L)lrH(2), where Cp(*) and L are abbreviations for the ligands (CH(3))(5)C(5) and (CH(3))(3)P, respectively. Irradiation with ultraviolet light causes the dihydride to lose H(2), generating the reactive intermediate Cp(*)lrL. This intermediate reacts rapidly with C-H bonds in every molecule so far tested (including alkanes) and leads to hydridoalkyliridium complexes Cp(*)(L)lr(R)(H). Evidence has been obtained that this C-H insertion, or oxidative addition, reaction proceeds through a simple three-center transition state and does not involve organic free radicals as intermediates. Thus the intermediate Cp(*)lrL reacts most rapidly with C-H bonds having relatively high bond energies, such as those at primary carbon centers, in small organic rings, and in aromatic rings. This contrasts directly with the type of hydrogen-abstraction selectivity that is characteristic of organic radicals. The hydridoalkyliridium products of the insertion reactions can be converted into functionalized organic molecules-alkyl halides-by treatment with mercuric chloride followed by halogens. Expulsion (reductive elimination) of the hydrocarbon from the hydridoalkyliridium complexes can be induced by Lewis acids or heat, regenerating the reactive intermediate Cp(*)lrL. Oxidative addition of the corresponding rhodium complexes Cp(*)RhL to alkane C-H bonds has also been observed, although the products formed in this case are much less stable and undergo reductive elimination at -20 degrees C. These and other recent observations provide an incentive for reexamining the factors that have been assumed to control the rate of reaction of transition metal complexes with C-H bonds-notably the need for electron-rich metals and the proximity of reacting centers.     

Highly regioselective amination of unactivated alkanes by hypervalent sulfonylimino-λ³-bromane

Amination of alkanes has generally required metal catalysts and/or high temperatures. Here we report that simple exposure of a broad range of alkanes to N-triflylimino-λ(3)-bromane 1 at ambient temperature results in C-H insertion of the nitrogen functionality to afford triflyl-substituted amines in moderate to high yields. Marked selectivity for tertiary over secondary C-H bonds was observed; primary (methyl) C-H bonds were inert. Addition of hexafluoroisopropanol to inhibit decomposition of 1 dramatically improved the C-H amination efficiencies. Second-order kinetics, activation parameters (negative activation entropy), deuterium isotope effects, and theoretical calculations suggest a concerted asynchronous bimolecular transition state for the metal-free C-H amination event.     

Molecular recognition in the selective oxygenation of saturated C-H bonds by a dimanganese catalyst

Although enzymes often incorporate molecular recognition elements to orient substrates selectively, such strategies are rarely achieved by synthetic catalysts. We combined molecular recognition through hydrogen bonding with C-H activation to obtain high-turnover catalytic regioselective functionalization of sp3 C-H bonds remote from the -COOH recognition group. The catalyst contains a Mn(mu-O)2Mn reactive center and a ligand based on Kemp's triacid that directs a -COOH group to anchor the carboxylic acid group of the substrate and thus modify the usual selectivity for oxidation. Control experiments supported the role of hydrogen bonding in orienting the substrate to achieve high selectivity.     

Gas-Phase Rates of Alkane C-H Oxidative Addition to a Transient CpRh(CO) Complex

The gas-phase irradiation of CpRh(CO)(2) (Cp = eta(5)-C(5)H(5)) was examined in order to study the rates of reaction of the 16-electron intermediates presumed to be involved in the C-H oxidative addition of alkanes. "Naked" (unsolvated) CpRh(CO) was detected, and direct measurements of the rates of reaction of this very short-lived complex with alkane C-H bonds were made. Activation of C-H bonds occurs on almost every collision for alkanes of moderate size, and intermediates in which the alkanes are bound to the metal centers, without their C-H bonds being fully broken, are implicated as intermediates in the overall reaction.     

Acyclic stereocontrol through the aldol condensation

For the scientist who wishes to synthesize complex organic compounds, the most difficult problem is often establishing the correct configuration at the various chiral centers as the synthesis is being carried out. In the past decade, there has been an increasing effort to find direct solutions to this problem, which is particularly acute in the synthesis of acyclic and other conformationally flexible molecules. One of the oldest organic reactions, the aldol condensation, is emerging as a powerful tool for use in achieving such stereocontrol.     

Reversible control of hydrogenation of a single molecule

Low-temperature scanning tunneling microscopy was used to selectively break the N-H bond of a methylaminocarbyne (CNHCH3) molecule on a Pt(111) surface at 4.7 kelvin, leaving the C-H bonds intact, to form an adsorbed methylisocyanide molecule (CNCH3). The methylisocyanide product was identified through comparison of its vibrational spectrum with that of directly adsorbed methylisocyanide as measured with inelastic electron tunneling spectroscopy. The CNHCH3 could be regenerated in situ by exposure to hydrogen at room temperature. The combination of tip-induced dehydrogenation with thermodynamically driven hydrogenation allows a completely reversible chemical cycle to be established at the single-molecule level in this system. By tailoring the pulse conditions, irreversible dissociation entailing cleavage of both the C-H and N-H bonds can also be demonstrated.     

Cytochrome P450 compound I: capture, characterization, and C-H bond activation kinetics

Cytochrome P450 enzymes are responsible for the phase I metabolism of approximately 75% of known pharmaceuticals. P450s perform this and other important biological functions through the controlled activation of C-H bonds. Here, we report the spectroscopic and kinetic characterization of the long-sought principal intermediate involved in this process, P450 compound I (P450-I), which we prepared in approximately 75% yield by reacting ferric CYP119 with m-chloroperbenzoic acid. The M?ssbauer spectrum of CYP119-I is similar to that of chloroperoxidase compound I, although its electron paramagnetic resonance spectrum reflects an increase in |J|/D, the ratio of the exchange coupling to the zero-field splitting. CYP119-I hydroxylates the unactivated C-H bonds of lauric acid [D(C-H) ~ 100 kilocalories per mole], with an apparent second-order rate constant of k(app) = 1.1 × 10(7) per molar per second at 4°C. Direct measurements put a lower limit of k ≥ 210 per second on the rate constant for bound substrate oxidation, whereas analyses involving kinetic isotope effects predict a value in excess of 1400 per second.     

Selective catalytic C-H alkylation of alkenes with alcohols

Alkenes and alcohols are among the most abundant and commonly used organic feedstock in industrial processes. We report a selective catalytic alkylation reaction of alkenes with alcohols that forms a carbon-carbon bond between vinyl carbon-hydrogen (C-H) and carbon-hydroxy centers with the concomitant loss of water. The cationic ruthenium complex [(C(6)H(6))(PCy(3))(CO)RuH](+)BF(4)(-) (Cy, cyclohexyl) catalyzes the alkylation in solution within 2 to 8 hours at temperatures ranging from 75° to 110°C and tolerates a broad range of substrate functionality, including amines and carbonyls. Preliminary mechanistic studies are inconsistent with Friedel-Crafts-type electrophilic activation of the alcohols, suggesting instead a vinyl C-H activation pathway with opposite electronic polarization.     

Net oxidative addition of C(sp3)-F bonds to iridium via initial C-H bond activation

Carbon-fluorine bonds are the strongest known single bonds to carbon and as a consequence can prove very hard to cleave. Alhough vinyl and aryl C-F bonds can undergo oxidative addition to transition metal complexes, this reaction has appeared inoperable with aliphatic substrates. We report the addition of C(sp(3))-F bonds (including alkyl-F) to an iridium center via the initial, reversible cleavage of a C-H bond. These results suggest a distinct strategy for the development of catalysts and promoters to make and break C-F bonds, which are of strong interest in the context of both pharmaceutical and environmental chemistry.     

Selectivity: a key to synthetic efficiency

The efficient synthesis of organic compounds requires the development of processes with enhanced selectivity. Selectivity is categorized according to chemical reactivity (chemoselectivity), orientation (regioselectivity), and spatial arrangement (diastereoselectivity and enantioselectivity). Recent developments in reduction-oxidation methods and C-C bond forming reactions illustrate some solutions to problems of selectivity. The design of selectivity-inducing groups and the increased role of main group and transition metals in enhancing selectivity are especially noted.     

Hydrogen as a Probe of Semiconductor Surface Structure: The Ge(111)-c(2 x 8) Surface

Hydrogen can be used as an effective probe of the structure of semiconductor surfaces. Such surfaces consist of bonds with varying degrees of bond strain, and hydrogen can react with each selectively depending on the reaction conditions. This selectivity is derived from a reduced barrier to reaction associated with strained bonds. In this manner, hydrogen can be used to pick apart the surface one bond type at a time, thereby revealing the structure of even complex multilayer reconstructions. This method is used to directly show that the rest-layer of the Ge(111)-c(2 x 8) surface has a bulk structure.     

结构脂质位置选择性酶法合成研究进展

甘油三酯中脂肪酸的组成、碳链长短和双键数目是影响油脂物理化学性质及营养价值的重要因素。脂肪酸在甘油骨架上的位置分布影响结构脂质的生理功能和营养价值。随着脂质功能的开发,结构脂质的研究备受关注。综述了酶法合成结构脂质反应中的脂肪酸酰化位置选择性的影响因素,重点评价了酶促酯交换反应中脂肪酶的催化特异性、反应的环境介质及不同的物理辅助条件等因素对脂肪酸酰化位置选择性的影响,并介绍了甘油三酯中脂肪酸酰化位置的分析检测方法。在此基础上,对酶法合成结构脂质的发展前景进行了展望。     

Bond-selective control of a heterogeneously catalyzed reaction

Energy redistribution, including the many phonon-assisted and electronically assisted energy-exchange processes at a gas-metal interface, can hamper vibrationally mediated selectivity in chemical reactions. We establish that these limitations do not prevent bond-selective control of a heterogeneously catalyzed reaction. State-resolved gas-surface scattering measurements show that the nu1 C-H stretch vibration in trideuteromethane (CHD3) selectively activates C-H bond cleavage on a Ni(111) surface. Isotope-resolved detection reveals a CD3:CHD2 product ratio > 30:1, which contrasts with the 1:3 ratio for an isoenergetic ensemble of CHD3 whose vibrations are statistically populated. Recent studies of vibrational energy redistribution in the gas and condensed phases suggest that other gas-surface reactions with similar vibrational energy flow dynamics might also be candidates for such bond-selective control.     

Empirical Explorations of SYNCHEM

During the past several years, a substantial body of experience has accumulated in the use of SYNCHEM, a large-scale program which is able to discover synthesis routes for relatively complex organic structures without on-line guidance on the part of its chemist user. These results indicate that the approach to computer-directed organic synthesis route discovery embodied in the program has been valid and reasonable, and that SYNCHEM is likely to be fruitful from the point of view of its intended users as well as for our research objectives in artificial intelligence. The experiments have revealed a number of insufficiencies in the program as well. Most of these are rectified in SYNCHEM2, a revised version of the program which includes, among other improvements, a more highly developed synthesis search algorithm and the routine consideration of stereochemistry.     

Scaffold proteins: hubs for controlling the flow of cellular information

The spatial and temporal organization of molecules within a cell is critical for coordinating the many distinct activities carried out by the cell. In an increasing number of biological signaling processes, scaffold proteins have been found to play a central role in physically assembling the relevant molecular components. Although most scaffolds use a simple tethering mechanism to increase the efficiency of interaction between individual partner molecules, these proteins can also exert complex allosteric control over their partners and are themselves the target of regulation. Scaffold proteins offer a simple, flexible strategy for regulating selectivity in pathways, shaping output behaviors, and achieving new responses from preexisting signaling components. As a result, scaffold proteins have been exploited by evolution, pathogens, and cellular engineers to reshape cellular behavior.     

Solvent-free oxidation of primary carbon-hydrogen bonds in toluene using Au-Pd alloy nanoparticles

Selective oxidation of primary carbon-hydrogen bonds with oxygen is of crucial importance for the sustainable exploitation of available feedstocks. To date, heterogeneous catalysts have either shown low activity and/or selectivity or have required activated oxygen donors. We report here that supported gold-palladium (Au-Pd) nanoparticles on carbon or TiO(2) are active for the oxidation of the primary carbon-hydrogen bonds in toluene and related molecules, giving high selectivities to benzyl benzoate under mild solvent-free conditions. Differences between the catalytic activity of the Au-Pd nanoparticles on carbon and TiO(2) supports are rationalized in terms of the particle/support wetting behavior and the availability of exposed corner/edge sites.     

Palladium-catalyzed aerobic dehydrogenation of substituted cyclohexanones to phenols

Aromatic molecules are key constituents of many pharmaceuticals, electronic materials, and commodity plastics. The utility of these molecules directly reflects the identity and pattern of substituents on the aromatic ring. Here, we report a palladium(II) catalyst system, incorporating an unconventional ortho-dimethylaminopyridine ligand, for the conversion of substituted cyclohexanones to the corresponding phenols. The reaction proceeds via successive dehydrogenation of two saturated carbon-carbon bonds of the six-membered ring and uses molecular oxygen as the hydrogen acceptor. This reactivity demonstrates a versatile and efficient strategy for the synthesis of substituted aromatic molecules with fundamentally different selectivity constraints from the numerous known synthetic methods that rely on substitution of a preexisting aromatic ring.     

Theory and modeling of stereoselective organic reactions

Theoretical investigations of the transition structures of additions and cycloadditions reveal details about the geometries of bond-forming processes that are not directly accessible by experiment. The conformational analysis of transition states has been developed from theoretical generalizations about the preferred angle of attack by reagents on multiple bonds and predictions of conformations with respect to partially formed bonds. Qualitative rules for the prediction of the stereochemistries of organic reactions have been devised, and semi-empirical computational models have also been developed to predict the stereoselectivities of reactions of large organic molecules, such as nucleophilic additions to carbonyls, electrophilic hydroborations and cycloadditions, and intramolecular radical additions and cycloadditions.